Cancer therapies comprise a wide range of therapeutic approaches, including surgery, radiation, and chemotherapy. While the various approaches allow a broad selection of treatments to be available to the medical practitioner to treat the cancer, existing therapeutics suffer from a number of disadvantages, such as a lack of selectivity of targeting cancer cells over normal, healthy cells, and the development of resistance by the cancer to the treatment.
Recent approaches based on targeted therapeutics, which interfere with cellular processes of cancer cells preferentially over normal cells, have led to chemotherapeutic regimens with fewer side effects as compared to non-targeted therapies such as radiation treatment.
Cancer immunotherapy has emerged as a promising therapeutic approach to complement existing standards of care. See, e.g., Miller, et al. Cancer Cell, 27, 439-449 (2015). Such immunotherapy approaches include the development of antibodies used to modulate the immune system to kill cancer cells.
For example, interaction of PD-1, a type I cell surface receptor, with either of its two ligands, PD-L1 or PD-L2, results in a dominant negative checkpoint signal that limits subsequent antigen receptor-driven cellular activation. The ligands for PD-1 are differentially expressed on various tissues and cell types, including antigen-presenting cells of the immune system, and are upregulated on many types of tumor cells. Upregulation of PD-L1 within the tumor microenvironment is a proposed mechanism of tumors to subvert protective anti-tumor immune responses by the host. Antibodies directed at PD-1 that block the interaction of the receptor with either of its ligands result in inhibition of negative signaling. In vitro inhibition of the PD-1 mediated checkpoint signal has been demonstrated to result in prolonged antigen-specific T cell activation. In vivo PD-1 blockade has been shown to enhance anti-tumor immune responses in both syngeneic mouse tumor models and in human clinical trials.
Anti-tumor immune responses in patients with solid tumors have been enhanced by anti-PD-1 treatment. There are two approved and marketed antagonistic anti-PD-1 monoclonal antibodies: nivolumab (OPDIVO®) and pembrolizumab (KEYTRUDA®), with approvals in the US and the European Union to treat diseases such as unresectable or metastatic melanoma and metastatic non-small cell lung cancer. Treatment of patients with these agents has resulted in anti-tumor responses as measured by improvement in either progression free survival and/or overall survival.
The recent failure of OPDIVO® to slow progression of advanced lung cancer in a treatment-naïve patient population in a clinical trial comparing OPDIVO® with conventional chemotherapy highlights the need for alternative approaches and additional cancer treatments to complement existing therapeutic standards of care.